The synthesis of well-defined polymers with controlled chain end functionalities is important for the achievement of nanotechnology. These polymers have been especially important as potential drug delivery vehicles. In the last decade, the use of various controlled polymerizations have resulted in well-defined copolymers with different designs. For example, nitroxide-mediated polymerization, dithio component-mediated reversible addition-fragmentation chain transfer and atom transfer radical polymerization (ATRP) are controlled processes, which offer control over molecular weight and molecular architecture (diblock, grafted or tapered copolymers). However, a few monomers such as vinyl acetate and N-vinyl-2-pyrrolidone (VP) do not form radicals stabilized by resonance and inductive effects, and therefore the polymerization of these monomers has not yet been performed efficiently by controlled radical polymerizations. Matyjaszewski et al. (Am. Chem. Soc. Symp. Ser. 685:258 1998 and J. Polym. Sci. Part A:Polym. Chem. 36:823-830 1998) reported the homopolymerization of VP using Me4Cyclam as a ligand. Chain end functionalities were difficult to obtain using the synthetic pathway described by Matyjaszewski et al.
The instant inventors are interested in functionalized and well-defined poly(N-vinyl-2-pyrrolidone) (PVP) as a replacement for poly(ethylene glycol) (PEG) in diverse drug delivery systems. Although a number of diblock or triblock copolymers can form micelles in aqueous solution, few among them are truly suitable as drug carriers due to biocompatibility issues [Alexandridis et al. Current Opinion Colloid & Interface Science 2:478-489 1997; Rapoport et al. J. Pharm. Sci. 91:157-170 2002; Kabanov et al. Adv. Drug Deliv. Rev. 54:223-233 2002; Nishiyama et al. Langmuir 15:377-383 1999; Kakizawa et al. Langmuir 18:4539-4543 2002; Katayose et al. Bioconjugate Chem. 8:702-707 1997; Yamamoto et al. J. Controlled Release 82:359-371 2002; Liggins et al. Adv. Drug Deliv. Rev. 54:191-202 2002; Kim et al. J. Controlled Release 72:191-202 2001; Yoo et al. J. Controlled Release 70:63-70 2001; Luo et al. Bioconjugate Chem. 13:1259-1265 2002; Lim Soo et al. Langmuir 18:9996-10004 2002; Gref et al. Science 263:1600-1603 1994 and Burt et al. Colloids Surf. B 16:161-171 1999]. Many studies have reported the use of polyester-block-poly(ethylene glycol) block copolymers [Yamamoto et al.; Liggins et al.; Kim et al.; Yoo et al.; Luo et al.; Lim Soo et al.; Gref et al. and Burt et al. journal citations, supra]. PEG is widely used as hydrophilic arm on the surface of nanoparticles [Kissel et al. Adv. Drug Deliv. Rev. 54:99-134 2002], liposomes [Gabizon et al. Adv. Drug Deliv. Rev. 24:337-344 1997] and polymeric micelles [Jones et al. Eur. J. Pharm. Biopharm. 48:101-111 1999; Kataoka et al. Adv. Drug Deliv. Rev. 47:113-131 2001 and Kabanov et al. Adv. Drug Deliv. Rev. 54:759-779 2002]. The PEG-based outer shell can actually prevent the nanocarrier uptake by the mononuclear phagocytic system via steric effects [Jones et al.; Kataoka et al. and Kabanov et al. journal citations; supra]. This prevention substantially improves the circulation time of polymeric micelles in the blood stream. In cancer treatment, this prolonged time generally results in a selective accumulation in a solid tumor due to the enhanced permeability and retention effect of the vascular endothelia at the tumor site [Yokoyama et al. Cancer Res. 50:1693-1700 1990; Yokoyama et al. Cancer Res. 51:3229-3236 1991; Kwon et al. J. Controlled Release 29:17-23 1994; Yokoyama et al. J. Controlled Release 50:79-92 1998 and Yamamoto et al. J. Controlled Release 77:27-38 2001]. However, since aggregation of nanoparticles with PEG as corona occurs during lyophilization, it features some limitations. Thus, PEG is not ideally suited for efficient use in drug delivery systems.
Functionalized and well-defined PVP is an ideal component for replacement of PEG in drug delivery systems. PVP has been proven to be biocompatible [Haaf et al. Polymer J. 17:143-152 1985] and has been extensively used in pharmaceutical industry. Particularly, PVP can be used as cryoprotectant [Doebbler et al. Cryobiology 3:2-11 1966] and lyoprotectant [Deluca et al. J. Parent. Sci. Technol. 42:190-199 1988]. Hence, replacing PEG with PVP in drug delivery systems might help to overcome some freeze drying problems.
Torchilin et al. [J. Microencapsulation 15:1-19 1998] pioneered the study of PVP as hydrophilic corona of liposomes. The design of polymeric micelles with PVP outer shell have presented promising features for pharmaceutical uses. Thus, Benahmed et al. [Pharm. Res. 18:323-328 2001] reported the preparation of PVP-based micelles consisting of degradable diblock copolymers. In the work of Benahmed et al., PVP synthesis using 2-isopropoxyethanol as chain transfer agent was inspired from by previous work of Ranucci et al. [Macromol. Chem. Phys. 196:763-774 1995 and Macromol. Chem. Phys. 201:1219-1225 2000]. However, this synthetic procedure produced a lack of control over molecular weight, and did not quantitatively provide hydroxyl-terminated PVP, which is essential for polymerizing DL-lactide [Benahmed et al. Pharm Res. 18:323-328 2001]. Moreover, the removal of 2-isopropoxyethanol from the polymer turned out to be difficult because of its high boiling point (42-44° C. at 13 mmHg) and its binding to PVP via hydrogen bonding [Haaf et al. Polymer J. 17:143-152 1985]. Alcohol entrapment into polymer might cause problems for subsequent reactions which require anhydrous and aprotic conditions such as the synthesis of poly(D,L-lactide). Sanner et al. [Proceeding of the International Symposium on Povidone, University of Kentucky: Lexington, Ky., 1983, pp. 20] reported the synthesis of hydroxyl-terminated PVP oligomers via free radical polymerization in isopropyl alcohol (IPA), using cumene hydroperoxide as an initiator. 1H-NMR spectra have shown that there were 1.3 end groups of 2-hydroxyisopropyl per chain. It is suggested that significant termination by bimolecular combination occurred, between either a primary solvent radical and the propagating chains [Liu et al. Macromolecules 35:1200-1207 2002].
U.S. Pat. No. 6,338,859 (Leroux et al.) discloses a class of poly(N-vinyl-2-pyrrolidone)-block-polyester copolymers. Such PVP block copolymers represent new biocompatible and degradable polymeric micellar systems which do not contain PEG, but which exhibit suitable properties as drug carriers. PVP shows remarkable diversity of interactions towards non-ionic and ionic cosolutes. Prior to the disclosure by Leroux et al., only a random graft copolymer, poly(N-vinyl-2-pyrrolidone)-graft-poly(L-lactide) had been described in the literature [Eguiburu et al. Polymer 37:3615-3622 1996].
In the synthesis of the amphiphilic diblock copolymer disclosed by Leroux et al. hydroxy-terminated PVP was prepared by radical polymerization using 2-isopropoxyethanol as a chain transfer agent. The block copolymer was obtained by anionic ring opening polymerization. Although the strategy of Leroux et al. works very well for the preparation of the desired amphiphilic diblock copolymers in the laboratory, several problems remain to be solved in order to achieve a scalable process. The use of crown ether and the need of dialysis and ultra-centrifugation for the copolymer purification are not desirable on an industrial scale. Furthermore, in the process disclosed by Leroux et al., the degree of functionalization of hydroxyl-terminated PVP was not assessed.
What is lacking in the art is a process for preparing hydroxyl-terminated PVP, and using such functionalized PVP to prepare amphiphilic PVP-block-polyester block copolymers as well as other diblock or triblock copolymers consisting of PVP as one block; wherein the molecular weight, polydispersity index and functionality of the PVP can be controlled and wherein the process can be carried out on an industrial scale.